Annual evaluation

 

Irrespective of the place where you live, you are asked to return to the Swiss Centre for Liver Diseases in Children of the Children’s Hospital of Geneva once per year for the follow-up, since all patients are submitted to an annual evaluation approximately on the anniversary of their transplantation. This is a routine evaluation performed by the transplant team, but individualised for every patient. This means that your child undergoes more or less analyses depending on his medical history and his current state of health. Irrespective of the annual evaluation, we recommend every patient having himself examined regularly by a paediatrician, an ophthalmologist, a dentist and a dermatologist (for the screening for skin cancer).

The annual evaluation comprises several analyses and examinations that are explained in detail below:

 

WEIGHT AND HEIGHT

Weight and height are the first measurements taken when a transplanted child is back for an evaluation. This data is very important for evaluating the child’s growth and catch-up in weight and height.

 

HAEMATOLOGICAL EVALUATION

The haematological evaluation comprises the complete blood count (CBC), the level of cyclosporine (Neoral), of tacrolimus (Prograf), of prednisone and of mycophenolate (Cellcept), as well as blood chemistry.

 

The complete blood count, blood gas analyses, haemostasis, CRP

The complete blood count includes the counts of C-reactive protein (CRP), reticulocytes, blood gas analysis and of haemostasis. It is used to detect any possible effects of the immunosuppressive agents on the three lines of blood cells: the white blood cells, the red blood cells and the platelets. It also enables us to reveal a possible anaemia, as well as an infectious or viral state. Other drugs may also influence the blood count.

The C-reactive protein (CRP) is a blood protein produced by the liver in case of infection. Thus, an increased level of CRP indicates the presence of an infection.

The reticulocytes are young red blood cells. Their increase indicates that the bone marrow makes up for anaemia.

The blood gas analysis is used to assess the acid-base status and thus the renal function.

The haemostasis counts provide a general overview of the liver function : they reflect the hepatocellular function best. In fact, the coagulation factors produced by the liver constitute a good reflection of its function, in particular the factor V and the factors VII and X (that depend on it since they are poorly synthesised in case of vitamin K deficiency).

 

The level of immunosuppressive agents

At the level prescribed to liver-transplanted children, these drugs never cause complete immunosuppression, we therefore had better speak of immunodepression. Nevertheless, these drugs have multiple side effects and, of course, reduce the resistance to infection, it is therefore extremely important to find the exact dose that enables us to walk on the fine line between the risk of rejection and the risk of infection.

 

Blood chemistry

The blood chemistry corresponds to the measurement of certain compounds in the blood and comprises the analysis of the following values:

Glucose : We check the glucose level in order to rule out a possible hyperglycaemia, since the anti-rejection treatments, in particular Prograf, Cellcept and Solumedrol, may cause increased glucose levels in the blood.

Sodium (Na), phosphates, urea and creatinine : These values reflect the kidney function and the fluid balance.

Aspartate aminotransferase (ASAT) and alanine aminotransferase (ALAT) : ASAT and ALAT are liver enzymes, their values are used to assess whether the liver cells are suffering.

Gamma glutamyltransferase (gamma-GT) : Gamma-GT is another liver enzyme. It is the finest marker for the biliary ducts and indicates whether the cells of the bile ducts are suffering. Elevated gamma-GT in the blood is a sign of cholestasis.

Bilirubin and conjugated bilirubin : Bilirubin is a yellow pigment whose abnormal accumulation in the blood and in the tissues (cholestasis) indicates icterus (or “jaundice”) and that may have various causes. Increased conjugated bilirubin in the blood is a sign of cholestasis as well. Normally, conjugated bilirubin is excreted by the bile into the intestine. In case of retention of conjugated bilirubin, whether intrahepatic or extrahepatic, it reaches the blood rather than the intestine.

Alkaline phosphatase : Alkaline phosphatase is a biliary marker in adults and a bone marker in children.

Calcium : We check the decrease in the calcium level in the blood which may be due to liver failure or immunosuppressive treatment. A calcium replacement therapy is administered when the calcium level is too low.

Calcitriol, also called 1,25-dihydroxycholecalciferol or 1,25-dihydroxyvitamin D : Calcitriol is a hormone produced from vitamin D by the liver and the kidney. It increases the calcium level in the blood and the uptake of calcium into the bones. When the analyses reveal disorders of the level of this hormone in the blood, a vitamin D replacement treatment is recommended.

Parathyroid hormone (PTH): PTH is a hormone produced by the parathyroid glands. Together with calcitriol, it plays a key role in the regulation of the phosphate and calcium metabolism and thus completes the evaluation of bone metabolism. An increase in PTH in the blood thus reveals problems associated with the phosphate and calcium metabolism.

Magnesium : The blood level of magnesium is affected by the immunosuppressive treatment as well. When its level in the blood decreases, daily substitution of magnesium is required.

Iron, retinol (vitamin A) and tocopherol (vitamin E) : Their blood levels are often reduced in children with liver disorders. In fact, like vitamin K, vitamin A and vitamin E need the presence of biliary acids in the intestine in order to be absorbed properly.

Albumin : Albumin is a protein produced by the liver. Its level in the blood reflects the liver’s capacity for synthesis and the child’s nutritional state.

Lipid profile : This profile may be altered by the taking of immunosuppressive agents and may also be affected by certain liver disorders and by malnutrition.

 

Immunological analyses

Immunoglobulins A, G and M (IgA, IgG and IgM) : Immunoglobulins are proteins that play a critical role in the interactions between the cells involved in the immune system. IgM are produced by the white blood cells, when they see a virus for the first time, and IgG are produced by the white blood cells, when they are repeatedly faced with the same virus. IgA are also produced by the white blood cells in the mucous membranes where they constitute a first line of immune defence against the toxins and infectious agents found for example in the intestine.

Anti-LKM antibody : antibodies present in case of so-called auto-immune hepatites.

Protein electrophoresis : distribution of proteins in the blood.

Anti-smooth muscle antibody : antibodies present in case of so-called auto-immune hepatites.

Anti-nuclear factor (ANF) : antibodies present in case of a large number of auto-immune diseases.

 

Virus serologies

Virus serology consists in evaluating the immunity against certain viruses or certain bacteria. It can also be used to ensure the effectiveness of a vaccination or to diagnose an auto-immune disease. In general, all transplanted patients have been vaccinated before the liver transplant, but since immunosuppression inhibits the immunological memory, it is necessary to check their state of immunity.

Cytomegalovirus (CMV) : This virus has an affinity for the liver and causes hepatitis. The virus per se is not necessarily pathogenic, since there is a very large number of carriers in the population. However, it may be more aggressive in a patient under immunosuppressive agents and may trigger rejections. We check the CMV level in the blood in order to treat it when the blood levels are elevated.

Adenovirus : Adenoviruses are viruses that are widespread in nature. They trigger generally inapparent or benign infections (pharyngitis, bronchitis, conjunctivitis, influenza, gastroenteritis, etc.), but they may result in serious diseases in an immunodepressed patient. Adenoviruses may cause liver disorders and thus explain a small alteration of the liver tests.

Epstein Barr virus (EBV: This virus can cause the proliferation of the white blood cells and might result in lymphoma. The levels of EBV in the blood are checked regularly, since, when they are elevated, we will reduce immunosuppression so that the organism can fight the virus.

Hepatitis A and B : The children are examined to verify whether they have immunity against hepatitis B shown by an antibody to HBsAg.

 

URINALYSES

The use of immunosuppressive agents potentially toxic for the kidneys requires frequent follow-ups and the tightest possible adjustment of drug treatment.

Creatinine clearance : The creatinine clearance measures the glomerular filtration rate, that is the filtration of blood by the glomerulus of the kidney. The creatinine level in the urine therefore is an indication of the quantity of blood filtered. When we want to have a reflection of glomerular filtration, we measure the creatinine clearance using a 24-hour urine collection. For multifactorial reasons, it is very low during the first month after the transplant and then normalises depending on the blood level of tacrolimus or cyclosporine. However, it is absolutely required to regularly check its level in the urine, since the toxic effects on the kidneys may make themselves felt in the long term.

Inulin clearance : Like creatinine, inulin is a molecule that can be used as a measure of the glomerular filtration rate using a 24-hour urine collection.

For a 24-hour urine collection, 24 hours are the desired duration, but 12 hours are already enough. A spot urine analysis is an immediate examination of the urine used to monitor the phosphate elimination rate and the Na reabsorption rate. Urinary sediment is the analysis of the deposit obtained by centrifugation of the urine sample. This examination provides us with information on the presence of proteins or cells in the urine.

 

LIVER BIOPSY

Liver biopsy allows us to have an image of the liver under microscope.

Indication: A liver biopsy must often be performed after the transplant. Indications vary, the most common being the disturbance of liver function tests and the need to confirm or invalidate a rejection. Other times, the biopsy is performed even without disturbance of the laboratory values, if deemed necessary by the hepatologist, and given that the liver function tests are not always indicators of the real situation of the liver.  Finally, protocol biopsies are performed 5 and 10 years after transplant, as well as before the transition to the adult team. These biopsies allow us to visualise the evolution of liver at a certain time after the transplant.

Technique: The procedure is made by a hepatologist under general anaesthesia in the operating room. After skin disinfection an incision of a few millimetres is made; a special needle for liver biopsies is inserted through this opening, which allows us to collect a sample of approximately 2 cm long and 1.5 mm in diameter. This tissue is then sent to the laboratory to be analysed.

Preparation: The liver biopsy is carried out after ultrasound. Ultrasound is performed by radiologists on the eve of or a few hours before the procedure and, like all ultrasounds of the liver, requires fasting of minimum 4 hours. It should be noted that a blood sample is required prior to the liver biopsy to check clotting. Sometimes, depending on the patient’s pathology, antibiotic treatment is necessary during the procedure and 24-48 hours afterwards.

Risks and consequences: The main risk of the liver biopsy is bleeding. This risk is not very common but it exists and is higher during the 24 hours after the procedure. For this reason hospital monitoring is essential for 24 hours. During this time the patient can eat as soon as anaesthesia allows it and he/she can move freely. A blood sample 4 hours after the procedure allows monitoring hemoglobin and platelets.

 

OTHER EXAMINATIONS INCLUDED IN THE EVALUATION

Electrocardiogram (ECG) : to evaluate the cardiac function of a child with hypertension.

24-hour blood pressure monitoring : to detect a possible arterial hypertension that would be secondary to the immunosuppressive treatment or that could reflect damage to the kidneys. When the physicians consider it to be indicated you will go home with a 24-hour blood pressure monitoring device to evaluate whether your child has hypertension. It is very important to perform this examination in his normal environment, outside the hospital which represents a stress factor and which may thus lead to incorrect diagnoses.

Chest X-ray : when your child had pulmonary disorders.

Determination of bone age : X-ray of the hand to determine whether skeletal maturity is proportional to the child’s chronological age.

Bone mineral density scan : children with liver disorders often have a delay in bone mineralization. From the age of 5 years on, we can perform a bone mineral density scan in order to evaluate whether a treatment is required.

Abdominal ultrasonography (Doppler ultrasound) : this examination is used to evaluate the graft, its vessels and the biliary ducts. It is also used to monitor ascites.

Psychological evaluation : the paedopsychiatric team works closely with the gastroenterological and surgical team to follow up children with hepatic disorders and their families. It normally intervenes at the pre-transplant evaluation, during the transplant period if necessary and then at the regular evaluations.

Evaluation of psychomotor development : the children are regularly evaluated by the team of the Development Department (Unité de Développement, UD). For linguistic reasons, German-speaking children are generally evaluated in their canton.